US5753503A - Human monoclonal anti-HIV-I-antibodies - Google Patents

Human monoclonal anti-HIV-I-antibodies Download PDF

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US5753503A
US5753503A US08/347,966 US34796694A US5753503A US 5753503 A US5753503 A US 5753503A US 34796694 A US34796694 A US 34796694A US 5753503 A US5753503 A US 5753503A
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hiv
antibody
human
antibodies
cell line
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Hermann W. D. Katinger
Ruediger von Baehr
Alois A. Jungbauer
Tomas Porstmann
Franz J. Steindl
Roland Grunow
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/08—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from viruses
    • C07K16/10—RNA viruses
    • C07K16/112—Retroviridae (F), e.g. leukemia viruses
    • C07K16/114—Lentivirus (G), e.g. human immunodeficiency virus [HIV], feline immunodeficiency virus [FIV] or simian immunodeficiency virus [SIV]
    • C07K16/1145—Env proteins, e.g. gp41, gp110/120, gp160, V3, principal neutralising domain [PND] or CD4-binding site
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
    • A61K47/6803—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
    • A61K47/6811—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates the drug being a protein or peptide, e.g. transferrin or bleomycin
    • A61K47/6817—Toxins
    • A61K47/6819—Plant toxins
    • A61K47/6825—Ribosomal inhibitory proteins, i.e. RIP-I or RIP-II, e.g. Pap, gelonin or dianthin
    • A61K47/6827—Ricin A
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
    • A61K47/6839—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting material from viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/08—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from viruses
    • C07K16/10—RNA viruses
    • C07K16/112—Retroviridae (F), e.g. leukemia viruses
    • C07K16/114—Lentivirus (G), e.g. human immunodeficiency virus [HIV], feline immunodeficiency virus [FIV] or simian immunodeficiency virus [SIV]
    • C07K16/1143—Gag-pol proteins, e.g. p17or p24
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/21—Immunoglobulins specific features characterized by taxonomic origin from primates, e.g. man

Definitions

  • This invention is in the field of immuhology and particularly concerns human monoclonal anti-HIV-I antibodies and immunochemicals made from these antibodies.
  • human monoclonal antibodies may present a new source of antibodies to be used in immunotherapy against infections and other diseases.
  • mAb of human origin instead of murine origin avoids the induction of antibody response in humans.
  • the Fc-part of murine antibodies has to be removed prior to injection in humans to minimize antibody response against heterogenous administered proteins.
  • Human monoclonal antibodies however present a part of the homologous proteins of human individuals.
  • HIV human immunodeficiency virus
  • AIDS acquired immunodeficiency syndrome
  • Human anti-HIV-monoclonal antibodies Human anti-HIV-monoclonal antibodies (Hu anti-HIV-I mAb)
  • the hu anti-HIV-I mAb used is of IgG 1 subclass produced according to known hybridization procedures described by R. Kennet et al. in "Monoclonal antibodies and functional cell lines; progress and applications”. Plenum Press (New York), 1984. Samples of hybridoma 3D6, 24G3 and 25C2 were deposited in ECACC, Porton Down, Salisbury SP4 OJG, UK. The ECACC accession numbers for the deposited hybridomas are; 87110301 (3D6), 90091702 (24G3) and 89120601 (25C2).
  • IgG and IgM isotypes were analyzed from the culture supernatant by a sandwich enzyme-linked immunosorbant assay (ELISA) with peroxidase conjugated anti-human IgG, IgM (heavy chain specific) antibodies in a known manner.
  • ELISA sandwich enzyme-linked immunosorbant assay
  • Immunoblot using HIV envelope proteins prepared from native virons Purified virus was denatured and reduced with 2.5% SDS and 5.0% 2-mercaptoethanol at 90° C. for 5 min and applied to a 10% polyacrylamide slab gel. After separation protein bands were electio-transferred into a nitrocellulose sheet (Schleicher & Schull, FRG). After blocking the sheet with 5% dry milk, strips were cut and immersed in 5 ml 1:2 diluted culture supernatant. Bound antibodies were detected by reacting with anti-human IgG antibodies labeled with HRP and staining with diaminobenzidine containing 0.1% NiCl 2 .
  • SDS gel electrophoresis was performed according to Laemmli, Nature 227 (1970), 680-685.
  • the electrophoretically separated envelope proteins derived from genetically engineered E. coli (L. H. Gosting, et al.: Journal of Clinical Microbiology 25 (1987), 845-848) were electro blotted to nitrocellulose. After blocking with 3% bovine serum albumin (BSA dissolved in PBS) the strips were immersed in samples diluted in PBS buffer (containing 0.1% Triton X-100, 1% BSA, 0.5% gelatine) overnight, washed 3 times and incubated with goat anti-human GAMMA-chain labeled with peroxidase.
  • BSA bovine serum albumin
  • the hybridization probe was the 32 P-labeled plasmid pBlur8 which contains a cloned Alu-sequence that is specific for human DNA and repeated about 300.000 times in the genome (Schmid et al., Science 216 (1982), 1065.
  • the membrane was washed 3 ⁇ in 100 ml 2 ⁇ SSC, 0.1% SDS for 5' at room temperature and 2 ⁇ in 200 ml 1 ⁇ SSC, 0.1% SDS for 30' at 60° C. and autoradiographed for 80 hours.
  • H9 cells Fixed HIV-I infected cells (H9 cells) were incubated with the hu anti-HIV mAb. Binding of the mAb was demonstrated by a second incubation after washing out unbound mAb with FITC labeled anti-human IgG.
  • Ricin is extracted from castor beans (Ricinus communis) by known methods. Ricin is extracted either from grinded whole castor beans (Ricinus communis) or from castor bean cake, which is a by-product of castor bean processing. The castor bean cake is defatted by extraction 3 times with 5 volumes of (v/w) 40%-60% petroleum ether. The air-dried material is then extracted overnight in phosphate buffered saline (PBS; 0.15M NaCl, 0.01M phosphate, pH 7.2). The extract is cleared by filtration through a nylon gauze followed by centrifugation at 1500 g for 1 hour. The clear supernatant is precipitated at 4° C. with saturated anmonium sulfate.
  • PBS phosphate buffered saline
  • the precipitate is collected and harvested by centrifugation (1500 g, 1 hour), redissolved in a minimum amount PBS and dialyzed against PBS until the extract is free from ammonium sulfate.
  • the affinity-purified and concentrated toxin is cleaved into A- and B-chain by a 5% 2-mercaptoethanol solution.
  • the toxin is incubated at a concentration of 5 mg/ml in 0.1M Tris/HCL buffer pH 8.5 completed with 2-mercapto-ethanol (5% end concentration) and galactose (0.5M end concentration) overnight at room temperature, followed by 2-3 hours at 37° C.
  • the toxin is transferred from the starting buffer (PBS) into the incubation buffer (Tris buffer) by gel chromatography on Sephadex G25 columns equilibrated with the incubation buffer.
  • the sample is applied to a DEAE-Sepharose fast flow column equilibrated with 0.1M Tris/HCl buffer pH 8.5.
  • the column is washed with 0.1M Tris/HCl buffer pH 8.5 until all unbound material is eluted.
  • the unbound material essentially pure A-chain, is collected and passed down an asialo-fetuin-Sepharose 4B column to remove contaminating toxin.
  • the asialo-fetuin-Sepharose 4B was prepared according to the recommendations of Pharmacia company.
  • the unbound material is collected and filter sterilized and stored at 4° C.
  • the DEAE-Sepharose fast flow is regenerated with a 0.1M Tris-HCl pH 8.5 containing 0.1M galactose and 1M NaCl.
  • the clarified and dialyzed toxin extract is further purified by lectin affinity chromatography.
  • the gel (Sepharose 4B, Pharmacia) is pretreated with 1M propionic acid at room temperature for at least 4 weeks to enhance its binding capacity for lectins.
  • the column chromatography should be operated at temperatures lower than 10° C. to optimize lectin binding.
  • the clarified and dialyzed extract is applied to a PBS-equilibrated acid pretreated Sepharose 4B column. After application of the sample, the column is washed with PBS until the UV-absorbance returns to the baseline.
  • the toxin is eluted together with other lectins with 100 mM galactose in PBS. This mixture is further separated by gel chromatography on Sephacryl S200HR. The sample volume should not exceed 3-4% of the bed total volume. The toxin is resolved completely from the other lectins under these conditions.
  • the toxin recovered from the affinity column is concentrated to 10 mg/ml by ultrafiltration (Milipore PTGC membrane) prior to application on Sephacryl S200 HR column.
  • the toxin peak was collected and filter sterilized.
  • the sterile toxin solution was stored deep frozen at -30° C. until cleavage into A and B-chain.
  • the isoelectric point of the hu anti-HIV-I mAb was determined by a described method. Pharmalytes were used as carrier ampholytes. The whole procedure was carried out according to the recommendation of the Pharmacia company (booklet: Isoelectric focussing, Pharmacia fine chemicals).
  • Light chains and subclass were determined by ELISA. Specific anti-human KAPPA-CHAIN antibodies labeled with alkaline phosphatase or specific anti-human G 1 , G 2 , G 3 and G 4 antibodies labeled with peroxidase were used.
  • the mixture was rocked for 1 hour at 4° C. and then diafiltrated at 4° C. against 0.01M sodium phosphate buffer containing 2.0M sodium chloride.
  • the bulk of the unconjugated A-chain was separated from the immunotoxin by gel chromatography on Sephacryl S200-HR. The column was equilibrated in 0.02M sodium phosphate containing 3M sodium chloride.
  • the fraction of the first peak which contained the immunotoxin was pooled and affinity-purified on an anti-human IgG-Sepharose 4B.
  • the immunotoxin was eluted from the affinity column with 3.5M magnesium chloride and extensively dialyzed against sodium chloride and against PBS.
  • Immunotoxins (0.2-2 mg/ml) were concentrated by ultrafiltration using PTGC membranes to end concentration necessary for testing. The final preparation was sterile filtered and stored in aliguots at -20° C. The immunotoxins were analyzed by SDS-PAGE under both reducing and non-reducing conditions. The substitution of the immunotoxin was determined by radioimmunoassay. An average substitution of 1-2 moles A-chain per mole antibody was observed.
  • a dilution series of hu anti-HIV mAb (in PBS with 1% BSA and 0.1% Triton X-100) was dispensed in flat-bottomed microtiter wells coated with purified HIV envelope proteins incubated overnight at 4° C. After washing out unbound material the bound conjugate was determined by reaction with 1,4 phenylenediamine. The developed colour was measured at 492 nm. As a calibration curve the optical density was plotted versus dilution. The dilution of the half saturation is calculated from this calibration curve.
  • Hu anti-HIV mAb at a dilution corresponding to the half maximum saturation was mixed with sera from patients suffering from AIDS or with sera from probands who were sero positive as determined by a conventional screening (ELISA) followed by a confirmation test (westernblot).
  • the mixture of the conjugate (at half maximal dilution) and the serum, from the probands were incubated in HIV envelope protein-coated microtiter wells, washed and stained.
  • optical density of these samples is compared to the anti HIV mAb at half maximum saturation. A value below the half maximum saturation indicates a competition between the human sera and the human monoclonal anti-HIV antibody.
  • the assay for neutralizing activity of the hu anti-HIV mAb was performed according to a known method (J. Virology 61 (1987) , 2024-2428), Nature 316 (1985), 72-74; Biotechnology 5 (1987) 940-946).
  • the neutralizing effect was also tested in the presence of the monoclonal antibody at variable dilutions.
  • test cell line used in the cytotoxicity tests were HIV-I infected H9 cells prepared as described above under "HIV-I neutralizing activity". Uninfected H9 cells were used as negative control. Cells harvested after a period of 6-9 days after virus inoculation were suspended in 1 ml medium.
  • FIG. 1A is an immunoblot of the human mAb produced by Hybridoma No. 3D6.
  • FIG. 1B is an immunoblot of the-human anti-HIV mAb produced by Hybridoma 3D6.
  • FIG. 1C is an immunoblot of the human anti-HIV mAb produced by Hybridoma 3DG.
  • FIG. 2 illustrates the detection of human DNA by hybridization.
  • FIGS. 3A-3B show the specific immunofluorescence of fixed HIV-I infected H9 cells.
  • FIG. 4 is a graph showing neutralizing activity of 3D6 antibody.
  • FIG. 5 shows the inhibition of protein synthesis as a measure of cytotoxicity.
  • FIGS. 1A, 1B and 1C The hu anti-HIV-I mAb produced by hybridoma cell line 3D6 is used as an example to illustrate the present invention. Immunoblots of the 3D6 antibody are shown in FIGS. 1A, 1B and 1C.
  • FIG. 1A HIV envelope proteins were prepared from native virons by SDS and 2-mercaptoethanol treatment.
  • FIG. 1B HIV envelope proteins were prepared from genetically engineered E. coli (according to a known procedures L. H. Gosting et al: Journal of Clinical Microbiology 25 (1987), 856-848).
  • FIG. 1C a commercially available blot strip (Du Pont Lot.: 70 44 128) was used.
  • the human origin of the monoclonal antibody is shown by the hybridization of 32 P-labeled plasmid pBlur8. Autoradiographs are shown in FIG. 2 with the DNA of the hybridoma cells. Also the reaction with anti-human IgG and human IgM antisera and the more specific sera for subclass determination verifies the human origin of the monoclonal antibodies.
  • letters a) through f) mark the different cell lines tested: a) 3D5; b) 3D9; c) 24G3; d) BJA-B (human lymphoid cell line, positive control; e) P3X63Ag/653 (murine myeloma, negative control; f) BUBTT (human bladder carcinoma, positive control.
  • the isotype of the monoclonal antibody produced by hybridoma 3D6 is G.
  • the subclass determined by ELISA is G1.
  • the isoelectric point, determined by isoelectric focussing using the Pharmacia system is in the range of pH 8.6.
  • FIG. 3 The HIV-I infected H9 cells were imaged with a sandwich of 3D6 antibody and anti-human IgG conjugated with FITC. Clones 3D6 and 3D5 are shown.
  • H9 cells In the presence of up to 1 ug/ml 3D6 antibody H9 cells could not be infected by 20 times TCID50 of HIV virons.
  • the monoclonal antibody 3D6 covalently linked with the ricin A-chain was used to demonstrate the cytotoxicity of the antibody.
  • the cytotoxicity was measured by 35 S-methionine uptake.
  • the immunotoxin consisting of a conjugate between 3D6 antibody and ricin A-chain, prepared as described above under "Materials and methods" specifically killed HIV-I infected H9 cells.
  • the inhibition of protein synthesis determined by 35 S-methionine uptake was taken as a measure for cytotoxicity.
  • the 35 S-methionine uptake is expressed in percent of the control (FIG. 5).
  • the TCID 50 of the immunotoxin is less than 10 mM.
  • a competitive EIA Enzyme immunoassay was chosen to compare the claimed monoclonal antibodies with naturally occurring antibodies in men after a HIV infection.
  • the 3D6 monoclonal antibody was conjugated with peroxidase and the dilution of the half maximum saturation was determined.
  • the 3D6 antibody at a dilution of half maximum saturation was mixed with different sera from seropositives without clinical manifestation of AIDS and with sera from patients suffering from AIDS or pre-AIDS in a ratio of 1:1.
  • the competition between the 3D6 antibody and the naturally occurring antibodies in blood are expressed in percent% of the half maximum saturation.
  • Table II shows the values from competitive EIA using a 3D6-antibody peroxidase conjugate and different sera.

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WO2005118887A2 (en) 2004-06-01 2005-12-15 Merck & Co., Inc. Human antibodies interacting with hiv gp41
EP2492279A1 (de) 2011-02-25 2012-08-29 Laboratorios Del. Dr. Esteve, S.A. Schnelles immunogenes Auswahlverfahren mittels Lentivirenanzeige
WO2012170765A2 (en) 2011-06-10 2012-12-13 Oregon Health & Science University Cmv glycoproteins and recombinant vectors
EP2568289A2 (de) 2011-09-12 2013-03-13 International AIDS Vaccine Initiative Immunselektion von rekombinantem vesikulärem Stomatitisvirus mit Expression von HIV-1-Proteinen durch Breitbandneutralisierungs-Antikörper
EP2586461A1 (de) 2011-10-27 2013-05-01 Christopher L. Parks Von einem eingehüllten Virus abgeleitete Virenpartikel
EP2679596A1 (de) 2012-06-27 2014-01-01 Simon Hoffenberg HIV-1 Env-Proteinvariante
EP2698377A1 (de) 2012-08-17 2014-02-19 Laboratorios Del. Dr. Esteve, S.A. Verbessertes schnelles Immunogene Auswahlverfahren für HIV gp120 Varianten
EP2848937A1 (de) 2013-09-05 2015-03-18 International Aids Vaccine Initiative Verfahren zur Identifizierung neuartiger HIV-1-Immunogene
EP2873423A2 (de) 2013-10-07 2015-05-20 International Aids Vaccine Initiative Lösliche hiv-1-hüllglykoproteintrimere
EP3069730A2 (de) 2015-03-20 2016-09-21 International Aids Vaccine Initiative Lösliche hiv-1-hüllglykoproteintrimere
EP3072901A1 (de) 2015-03-23 2016-09-28 International Aids Vaccine Initiative Lösliche hiv-1-hüllglykoproteintrimere
WO2017093985A1 (en) 2015-12-05 2017-06-08 Centre Hospitalier Universitaire Vaudois Hiv binding agents
EP3187585A1 (de) 2010-03-25 2017-07-05 Oregon Health&Science University Cmv-glycoproteine und rekombinante vektoren
WO2020012435A1 (en) 2018-07-13 2020-01-16 Lausanne University Hospital Hiv binding agents
WO2021009697A2 (en) 2019-07-15 2021-01-21 Lausanne University Hospital Hiv binding agents

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AT396939B (de) * 1990-05-29 1993-12-27 Alois Dipl Ing Dr Jungbauer Komplexes virales antigen von hiv-1 bindendes rekombinantes protein
HUT62316A (en) * 1990-09-25 1993-04-28 Hiver Ltd Process for producing aids vaccine and for diagnosing aids
GB9113475D0 (en) * 1991-06-21 1991-08-07 Hafslund Nycomed As Chemical compound
US5665569A (en) * 1991-08-22 1997-09-09 Nissin Shokuhin Kabushiki Kaisha HIV immunotherapeutics
AU2308595A (en) * 1995-04-19 1996-11-07 Polymun Scientific Immunobiologische Forschung Gmbh Monoclonal antibodies against hiv-1 and vaccines made thereo f

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Cited By (21)

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ATE135743T1 (de) 1996-04-15
DE3855134T2 (de) 1996-10-02
EP0355140A1 (de) 1990-02-28
JPH02502251A (ja) 1990-07-26
DE3855134D1 (de) 1996-04-25
EP0355140B1 (de) 1996-03-20
WO1989004370A1 (en) 1989-05-18

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